CHAPTER 20 PERIPHERAL ARTERIAL DISEASE, FOOT ULCERS, LOWER EXTREMITY AMPUTATIONS, AND DIABETES Edward J. Boyko, MD, MPH, Matilde Monteiro-Soares, DPM, PhD, and Stephanie G.B. Wheeler, MD, MPH Dr. Edward J. Boyko is Professor at the University of Washington and Staff Physician at the Veterans Affairs Puget Sound, Seattle, WA. Dr. Matilde Monteiro-Soares is an Investigator at the Center for Health Technology and Services Research (CINTESIS) and an Instructor in the Department of Community Medicine Information and Health Decision Sciences (U753-FCT), Oporto Faculty of Medicine, Oporto, Portugal. Dr. Stephanie G.B. Wheeler is Associate Professor at the University of Washington and Staff Physician, Veterans Affairs Puget Sound, Seattle, WA. SUMMARY Peripheral arterial disease (PAD) is common among persons with diabetes, and estimates of prevalence range from 10% to 20%. The condition is often asymptomatic. Persons with diabetes are at increased risk for PAD and often have more distal vascular disease than persons without diabetes. PAD is associated with substantial morbidity, including pain and functional impairment, amputation, and higher risk of death. Diabetic foot ulcer (DFU) occurs commonly in persons with diabetes, with a lifetime prevalence estimated between 12% and 25%. Healing of DFU may take months to years, and often these lesions lead to lower extremity amputation (LEA). The leading cause of DFU is neuropathy, with contributions from multiple other risk factors, including PAD, diabetes duration and control, and self-care factors. Although diabetes accounted for the majority of all LEA in the United States in 1997, the frequency of hospitalizations for amputation among persons also coded as having diabetes fell dramatically between 1996 and 2008, from approximately 11 to 4 per 1,000 persons hospitalized. Although reduced, this rate is approximately sevenfold higher compared to persons without diabetes. PAD, DFU, and LEA have a considerable negative impact on both the functional status and survival of persons with diabetes in the United States. PERIPHERAL ARTERIAL DISEASE INTRODUCTION endothelial cell dysfunction, abnormalities atheroma development. Hyperglycemia Peripheral arterial disease (PAD) refers in vascular smooth muscle cell function, activates inflammatory mediators and to partial or complete obstruction of the platelet abnormalities, and a hyperco- reactive oxygen products that are associ- peripheral arteries, typically the arteries agulable state (1,2,3). Nitric oxide (NO) ated with abnormal migration of vascular in the legs. The most common symptom is an important mediator of endothelial smooth muscle cells, so that advanced of PAD is intermittent claudication, which function due to its effects on vasodilation, atherosclerotic lesions in diabetic patients is calf and lower extremity pain that leukocyte-vascular wall interactions, and have fewer vascular smooth muscle cells develops with walking or other exertion platelet aggregation. Hyperglycemia compared with lesions in those without and is relieved by rest. However, the contributes to the loss of NO homeostasis diabetes. This can promote atherosclerotic majority of persons with PAD are asymp- by blocking endothelial cell NO synthase lesion formation and plaque instability. tomatic. PAD is more common among (4) and increasing production of reactive Glucose entry into platelets is not depen- persons with diabetes due to the higher oxygen species accompanied by vascular dent on insulin, so glucose levels in the risk for arterial atherosclerosis associated inflammation (5). Insulin resistance leads platelet are similar to intravascular levels with this metabolic disorder. to increased free fatty acid levels, which and can lead to changes associated with activate protein kinase C, inhibit phos- accelerated atherogenesis, including oxida- PATHOPHYSIOLOGY OF phatidylinositol-3 kinase, and increase tive stress, increased platelet aggregation, ATHEROSCLEROSIS IN DIABETES production of reactive oxygen species. and decreased levels of endogenous inhib- Diabetes is associated with an increased Increases in these proinflammatory factors, itors of platelet activity. Hyperglycemia risk for atherogenesis and vascular together with the loss of NO homeostasis increases blood coagulability and impairs inflammation, caused by hyperglycemia, and increased local oxidative stress, are fibrinolysis through increased production excess free fatty acids, insulin resistance, associated with the transformation of of tissue factor, a potent procoagulant. and other factors. Inflammation and leukocytes into foam cells (3). Transition Hyperglycemia also increases plasma atherogenic activity are associated with to foam cells is an important early step in concentrations of factor VII and Received in final form January 6, 2015. 20–1 DIABETES IN AMERICA, 3rd Edition plasminogen activator inhibitor type 1 and TABLE 20.1. Mean Ankle-Brachial Index Among Adults Age ≥40 Years, Overall and by decreases endogenous anticoagulants, Diabetes Status, U.S., 1999–2004 such as antithrombin III and protein C. MEAN (STANDARD ERROR) Diagnosed Undiagnosed Differences in Pathophysiology Overall All Diabetes Diabetes Diabetes No Diabetes Compared to Persons Without Diabetes Right side 1.12 (0.003) 1.10 (0.005) 1.09 (0.006) 1.10 (0.012) 1.13 (0.004) Arterial disease in people with diabetes is Left side 1.13 (0.003) 1.11 (0.005) 1.11 (0.006) 1.11 (0.013) 1.13 (0.003) both morphologically and physiologically Diagnosed diabetes is based on self-report. Undiagnosed diabetes is defined as A1c ≥6.5% or fasting plasma glucose different than in persons without diabetes ≥126 mg/dL. Conversions for A1c and glucose values are provided in Diabetes in America Appendix 1 Conversions. (6,7,8). The femoropopliteal arterial A1c, glycosylated hemoglobin. All relative standard errors ≤30% segments are most often affected, as in SOURCE: National Health and Nutrition Examination Surveys 1999–2004 nondiabetic patients. However, smaller vessels below the knee, including the FIGURE 20.1. Prevalence of Peripheral Arterial Disease Among Adults Age ≥40 Years, by profunda femoris, popliteal, anterior tibial, Diabetes Status, U.S., 1999–2004 peroneal, and posterior tibial arteries, are more severely affected in diabetic than in Overall All diabetes Diagnosed diabetes nondiabetic patients (2,8,9,10), with a high Undiagnosed diabetes No diabetes prevalence of diffuse rather than focal 18 lesions. In addition, medial calcification 15 of the tibial and peroneal arteries is more 12 common. Diabetes is associated with a propensity to earlier arterial calcification, 9 increased thrombogenicity, and generally 6 poorer prognosis. 3 Peripheral arterial disease (%) 0 DEFINITION AND Diabetes Status MEASUREMENT OF PAD Peripheral arterial disease is defined as ankle-brachial index <0.9 on either leg. Diagnosed diabetes is based on PAD refers to narrowing of the vascular self-report. Undiagnosed diabetes is defined as A1c ≥6.5% or fasting plasma glucose ≥126 mg/dL. Conversions lumen resulting in a reduction in blood for A1c and glucose values are provided in Diabetes in America Appendix 1 Conversions. Error bars represent 95% supply that leads to inadequate oxygen- confidence intervals. See Table 20.2 for further details. A1c, glycosylated hemoglobin. All relative standard errors ≤30% ation of the tissues of the lower extremity. SOURCE: National Health and Nutrition Examination Surveys 1999–2004 The most common cause of PAD is athero- sclerosis, in which the arterial lumen Noninvasive Measurement cutoff of 0.80. Severe obstruction requiring becomes occluded by plaque arising from The ankle-brachial index (ABI) is a noninva- vascular surgery evaluation is usually the intima. This process largely affects the sive, simple to perform, inexpensive, and recommended for a value <0.4 or <0.5. large and medium-sized arteries, usually widely used method for the assessment of at branch points and bifurcations (10,11). arterial blood flow to the lower extremity. In persons with diabetes, calcification of The ABI is measured in a supine patient by the tibial and peroneal arteries may render Invasive Measurement obtaining the brachial and ankle systolic them noncompressible and produce a Visualization of the arterial vasculature is pressures using a 5–7 MHz handheld falsely elevated ABI considerably greater possible via radiographic contrast angi- Doppler device. Both the posterior tibial than 1.0 (10). Symptoms of PAD may ography, which is considered the gold and dorsalis pedis systolic pressures should therefore occur even with an ABI >0.9, standard for vascular disease diagnosis. be obtained, because adequate flow in if noncompressible, calcified vessels Due to its invasive nature and the risk either of these arterial beds is sufficient to result in falsely high readings of the ankle of kidney injury, radiographic contrast perfuse the foot. The ABI is calculated by systolic blood pressure (14). The phenom- angiography is rarely used in clinical diag- dividing the higher of the posterior tibial enon of greater frequency of calcified, nosis other than in the setting of planned or dorsalis pedis systolic pressures by the noncompressible arteries in diabetes may revascularization, where it is performed to higher of either of the brachial systolic explain the similar values for mean ABI precisely localize anatomic arterial obstruc- pressures (12,13). The normal ABI can be by diabetes status seen in new analyses tions. Magnetic resonance angiography is defined as